Enhanced Cytotoxic Effect of TAT-PLGA-Embedded DOXO Carried by Biomimetic Magnetic Nanoparticles upon Combination with Magnetic Hyperthermia and Photothermia.

Ylenia Jabalera,Massimiliano Perduca,Concepcion Jimenez-Lopez,Guillermo R Iglesias,Salvatore Calogero Gaglio,María P Carrasco-Jiménez,Alberto Sola-Leyva

doi:10.3390/pharmaceutics13081168

Ylenia Jabalera, Massimiliano Perduca + Show 5 more

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https://doi.org/10.3390/pharmaceutics13081168

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Abstract

The synergy between directed chemotherapy and thermal therapy (both magnetic hyperthermia and photothermia) mediated by a nanoassembly composed of functionalized biomimetic magnetic nanoparticles (BMNPs) with the chemotherapeutic drug doxorubicin (DOXO) covered by the polymer poly(lactic-co-glycolic acid) (PLGA), decorated with TAT peptide (here referred to as TAT–PLGA(DOXO-BMNPs)) is explored in the present study. The rationale behind this nanoassembly lies in an optimization of the nanoformulation DOXO-BMNPs, already demonstrated to be more efficient against tumor cells, both in vitro and in vivo, than systemic traditional therapies. By embedding DOXO-BMNPs into PLGA, which is further functionalized with the cell-penetrating TAT peptide, the resulting nanoassembly is able to mediate drug transport (using DOXO as a drug model) and behaves as a hyperthermic agent (induced by an alternating magnetic field (AMF) or by laser irradiation with a laser power density of 2 W/cm2). Our results obtained using the HepG2 cell line show that there is a synergy between chemotherapy and thermal therapy that results in a stronger cytotoxic effect when compared to that caused by the soluble DOXO. This is probably due to the enhanced DOXO release occurring upon the application of the thermal therapy, as well as the induced local temperature rise mediated by BMNPs in the nanoassembly following exposition to AMF or to near-infrared (NIR) laser irradiation. These results represent a proof of concept demonstrating that TAT–PLGA(DOXO-BMNPs) can be used to efficiently combine therapies against tumor cells, which is a step forward in the transition from systemic to local treatments.

Highlights

We demonstrated that poly(lactic-co-glycolic acid) (PLGA) and/or TAT–PLGA covering of biomimetic magnetic nanoparticles (BMNPs) does improve the cell uptake of the nanoparticles, does not shelter the magnetic properties of the BMNPs, and maintains their ability to behave as hyperthermic agents
atomic force microscopy (AFM) images of TAT–PLGA(DOXO-BMNPs) (Figure 1A) showed nanoassemblies with a spherical shape that exhibited a diameter of 210 ± 50 nm; this size was further confirmed by nanoparticle tracking analysis (NTA) analysis (175 ± 50 nm)
W/cm2 for 600 s (Figure 7), a significant reduction in HepG2 cell viability, even higher than that caused by soluble DOXO, was observed (Figure 6). Both the temperature increases (Figure 3) and the highest DOXO release observed following combination with photothermia (Figure 4B) may have accounted for the higher cytotoxicity of the TAT–PLGA(DOXO-BMNPs) nanoassembly. These results are promising, since they demonstrate that the TAT–PLGA(DOXOBMNPs) nanoassembly, when exposed to an alternating magnetic field (AMF) or, even better, to photothermia, could be able to reach a comparable antiproliferative efficiency to that caused by soluble DOXO, but through a directed local versus systemic therapy

Summary

Introduction

The control that MamC exerts over the nucleation and growth of the crystals results in the formation of magnetite crystals of about 40 nm in size. This size increase with respect to the synthetic ones is enough to increase the magnetic moment per particle while maintaining their superparamagnetism (i.e., they behave as nonmagnetic in the absence of an external magnetic field, but respond with a maximized magnetic susceptibility once an external magnetic field is applied) [9]

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